Phase II Study of Pegylated Arginine Deiminase for Nonresectable and Metastatic Hepatocellular Carcinoma

Glazer, Evan S.; Piccirillo, Mauro; Albino, Vittorio; Giacomo, Raimondo Di; Palaia, Raffaéle; Mastro, Angelo Antonio; Beneduce, Gerardo; Castello, Giuseppe; Rosa, Vincenzo De; Petrillo, Antonella; Ascierto, Paolo A.; Curley, Steven A.; Izzo, Francesco

doi:10.1200/jco.2009.26.7765

Cited by 168 publications

(127 citation statements)

References 25 publications

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“…A phase I dose escalation study which combined Adi-PEG 20 with cisplatin and pemetrexed provided a signal of efficacy with a 78% response rate (7 out of 9 patients) (163). These findings are consistent with demonstrated efficacy of arginine depletion therapy in other malignancies (164)(165)(166)(167). A phase 2/3 study is currently recruiting patients with MPM with low ASS1 expression to evaluate the efficacy of Adi PEG 20 in combination with pemetrexed and cisplatin (clinicaltrials.gov NCT02709512).…”

Section: Arginine Depletionsupporting

confidence: 53%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

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Section: Arginine Depletionsupporting

confidence: 53%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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“…The first is arginine deiminase (ADI)-polyethylene glycol, a PEG form of mycoplasma-derived arginine deiminase. 61 ADI converts arginine into citrulline and ammonia, potentially leading to toxic hyperammonemia, and ensuing neutropenia. 61 The bacterial origin of the molecule leads to neutralizing antibody formation and intramuscular injection site hypersensitivity reactions, limiting continued drug administration and a failure to sustain adequately low plasma arginine.…”

Section: Discussionmentioning

confidence: 99%

“…61 ADI converts arginine into citrulline and ammonia, potentially leading to toxic hyperammonemia, and ensuing neutropenia. 61 The bacterial origin of the molecule leads to neutralizing antibody formation and intramuscular injection site hypersensitivity reactions, limiting continued drug administration and a failure to sustain adequately low plasma arginine. 62,63 An alternative PEG human arginase has also been described, in which the enzyme cofactor has been replaced with cobalt to increase arginase activity, 52 but unfortunately seems in early preclinical studies to be significantly more toxic.…”

Section: Discussionmentioning

confidence: 99%

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Mussai

Egan

Higginbotham-Jones

et al. 2015

Blood

139

153

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Key Points• Arginase depletion with BCT-100 pegylated recombinant human arginase is cytotoxic to AML blasts.Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML. (Blood. 2015;125(15):2386-2396

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“…L-Arginine and L-citrulline were resolved with a PCX 5200 postcolumn derivitization instrument (Pickering Laboratories) at 39°C reaction temperature and a fluorescence detector. All reagents, including the buffer and column, were used as suggested by Pickering Laboratories and as described previously (1,2,9).…”

Section: Metabolite Analysis Of Blood Samplesmentioning

confidence: 99%

Novel Mechanistic Insights into Arginine Deiminase Pharmacology Suggest ¹⁸F-FDG Is Not Suitable to Evaluate Clinical Response in Melanoma

Stelter¹,

Evans²,

Jungbluth³

et al. 2012

J Nucl Med

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Because of deficiencies in L-arginine biosynthesis, some cancers are susceptible to therapeutic intervention with arginine deiminase (ADI), an enzyme responsible for consuming the dietary supply of L-arginine to deprive the disease of an essential nutrient. ADI is currently being evaluated in several clinical trials, and fully realizing the drug's potential will depend on invoking the appropriate metrics to judge clinical response. Without a clear biologic mandate, PET/CT with 18 F-FDG is currently used to monitor patients treated with ADI. However, it is unclear if it can be expected that 18 F-FDG responses will indicate (or predict) clinical benefit. Methods: 18 F-FDG responses to ADI therapy were studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was also studied, with a particular emphasis on biologic pathways known to regulate 18 F-FDG avidity. Results: Although proliferation of SK-MEL 28 was potently inhibited by ADI treatment in vitro and in vivo, no clear declines in 18 F-FDG uptake were observed. Further investigation showed that ADI treatment induces the posttranslational degradation of phosphatase and tensin homolog and the activation of the PI3K signaling pathway, an event known to enhance glycolysis and 18 F-FDG avidity. A more thorough mechanistic study showed that ADI triggered a complex mechanism of cell death, involving apoptosis via poly (ADP-ribose) polymerase cleavage-independent of caspase 3. Conclusion: These findings suggest that some unexpected pharmacologic properties of ADI preclude using 18 F-FDG to evaluate clinical response in melanoma and, more generally, argue for further studies to explore the use of PET tracers that target apoptotic pathway activation or cell death.

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Phase II Study of Pegylated Arginine Deiminase for Nonresectable and Metastatic Hepatocellular Carcinoma

Abstract: Pegylated ADI is a promising drug that capitalizes on a significant enzymatic deficiency in HCC. It is safe, well tolerated, and may benefit patients with unresectable HCC.

Cited by 168 publications

References 25 publications

Novel systemic therapy against malignant pleural mesothelioma

Novel systemic therapy against malignant pleural mesothelioma

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Novel Mechanistic Insights into Arginine Deiminase Pharmacology Suggest ¹⁸F-FDG Is Not Suitable to Evaluate Clinical Response in Melanoma

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Phase II Study of Pegylated Arginine Deiminase for Nonresectable and Metastatic Hepatocellular Carcinoma

Abstract: Pegylated ADI is a promising drug that capitalizes on a significant enzymatic deficiency in HCC. It is safe, well tolerated, and may benefit patients with unresectable HCC.

Cited by 168 publications

References 25 publications

Novel systemic therapy against malignant pleural mesothelioma

Novel systemic therapy against malignant pleural mesothelioma

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Novel Mechanistic Insights into Arginine Deiminase Pharmacology Suggest 18F-FDG Is Not Suitable to Evaluate Clinical Response in Melanoma

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Product

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Novel Mechanistic Insights into Arginine Deiminase Pharmacology Suggest ¹⁸F-FDG Is Not Suitable to Evaluate Clinical Response in Melanoma